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The addition of evolocumab, a PCSK9 inhibitor, to statin therapy over several years significantly reduced cardiovascular morbidity and mortality in patients with clinically evident atherosclerotic cardiovascular disease, according to results from the FOURIER trial presented on Friday, March 17 during the first Late Breaking Clinical Trial session of ACC.17 in Washington, DC and simultaneously published in the New England Journal of Medicine.

Between February 2013 and June 2015, the study enrolled 27,564 patients with cardiovascular disease and on a moderate- to high-intensity statin regimen at 1,272 sites in 49 countries. Most patients (81 percent) had a history of heart attack, 19 percent had suffered an ischemic stroke and 13 percent had symptomatic peripheral artery disease. The median baseline LDL cholesterol (LDL-C) was 92 mg/dL. To be included, patients had to have an LDL-C ≥70 mg/dL or a non-high density lipoprotein cholesterol ≥100 mg/dL and be on optimized statin therapy. Patients who had had an acute heart attack or stroke within the previous four weeks and those with advanced heart failure, uncontrolled heart rhythm disorders, upcoming cardiac surgery and end-stage kidney disease were excluded.

Researchers randomly assigned patients (1:1) to receive subcutaneous injections of evolocumab (either 140 mg every two weeks or 420 mg every month based on patient preference) or matching placebo. They were followed every 12 weeks for routine health assessments, lab work and a resupply of the study drug.

Results showed evolocumab reduced LDL-C by 59 percent from a median of 92 to 30 mg/dL, which remained steady throughout the duration of the study. The primary endpoint – a composite of heart attack, stroke, hospitalization for angina, revascularization or cardiovascular death – occurred in 11.3 percent of the placebo group and 9.8 percent of the evolocumab group, translating to a 15 percent reduction. Researchers also saw a 25 percent reduction in the study's more serious secondary endpoint–cardiovascular death, heart attack or stroke–after the first year. The trial confirms trends observed in earlier open-label studies.

When examining individual outcomes, there was no effect on cardiovascular mortality by itself, but there was a statistically significant 27 percent reduction in heart attack and a 21 percent reduction in stroke. According to the study authors, reductions in the primary and key secondary endpoints were consistent across all the key subgroups, including age, sex, different types of cardiovascular disease, intensity of statin therapy, dosing regimen of evolocumab and baseline LDL-C levels, including those with the lowest quartile of LDL cholesterol–starting at 74 mg/dL–in whom evolocumab reduced LDL down to 22 mg/dL.

"With this trial, we now have definitive data that by adding evolocumab to a background of statin therapy, we can significantly improve cardiovascular outcomes and do so safely," said Marc S. Sabatine, MD, FACC, the Lewis Dexter, MD Distinguished Chair in Cardiovascular Medicine at Brigham and Women's Hospital in Boston, chair of the Thrombolysis in Myocardial Infarction (TIMI) study group and the study's lead author. "I think these results are very good news for patients with atherosclerotic disease, who remain at high risk for these events."

The rate of adverse events, including allergic reactions, neurocognition, new-onset diabetes and muscle-related problems, were the same in both study arms. Rates of injection site reactions were slightly more common with evolocumab (2.1 vs. 1.6 percent), but the vast majority were mild, and the overall rates of stopping the study drug due to suspected treatment-related adverse events were low and similar in both groups (1.6 and 1.5 percent). Researchers also looked at whether patients receiving evolocumab generated an undesired immune response to the treatment; only 0.3 percent developed antibodies that could bind evolocumab and none interfered with the drug.

"We've never been able to plumb these depths before. These data strongly suggest that patients benefit from lowering LDL-C well below current targets," Sabatine said. "We need to treat LDL-C more aggressively, and now we have a new validated means to do so."

This study is limited by its relatively short follow up and that it only studied patients with known cardiovascular disease. Sabatine said future studies would need to examine PCSK9 inhibitors in other high-risk populations not addressed in this study, for example, in patients with diabetes but without known cardiovascular disease.